Nishijima et al. Trials (2018) 19:593 https://doi.org/10.1186/s13063-018-2974-z

STUDY PROTOCOL Open Access

Traumatic injury clinical trial evaluatingtranexamic acid in children (TIC-TOC): studyprotocol for a pilot randomized controlledtrial

Daniel K. Nishijima1*, John VanBuren2, Hilary A. Hewes3, Sage R. Myers4, Rachel M. Stanley5, P. David Adelson6,Sarah E. Barnhard7, Matthew Bobinski8, Simona Ghetti9, James F. Holmes1, Ian Roberts10, Walton O. Schalick III11,Nam K. Tran12, Leah S. Tzimenatos1, J. Michael Dean2, Nathan Kuppermann13 for the TIC-TOC Collaborators of thePediatric Emergency Care Applied Research Network

Abstract

Background: Trauma is the leading cause of morbidity and mortality in children in the United States. Theantifibrinolytic drug tranexamic acid (TXA) improves survival in adults with traumatic hemorrhage, however,the drug has not been evaluated in a clinical trial in severely injured children. We designed the TraumaticInjury Clinical Trial Evaluating Tranexamic Acid in Children (TIC-TOC) trial to evaluate the feasibility of conducting aconfirmatory clinical trial that evaluates the effects of TXA in children with severe trauma and hemorrhagic injuries.

Methods: Children with severe trauma and evidence of hemorrhagic torso or brain injuries will be randomized toone of three arms: (1) TXA dose A (15 mg/kg bolus dose over 20 min, followed by 2 mg/kg/hr infusion over 8 h),(2) TXA dose B (30 mg/kg bolus dose over 20 min, followed by 4 mg/kg/hr infusion over 8 h), or (3) placebo. Wewill use permuted-block randomization by injury type: hemorrhagic brain injury, hemorrhagic torso injury, andcombined hemorrhagic brain and torso injury. The trial will be conducted at four pediatric Level I trauma centers.We will collect the following outcome measures: global functioning as measured by the Pediatric Quality of Life(PedsQL) and Pediatric Glasgow Outcome Scale Extended (GOS-E Peds), working memory (digit span test), totalamount of blood products transfused in the initial 48 h, intracranial hemorrhage progression at 24 h, coagulationbiomarkers, and adverse events (specifically thromboembolic events and seizures).

Discussion: This multicenter trial will provide important preliminary data and assess the feasibility of conductinga confirmatory clinical trial that evaluates the benefits of TXA in children with severe trauma and hemorrhagicinjuries to the torso and/or brain.

Trial registration: ClinicalTrials.gov registration number: NCT02840097. Registered on 14 July 2016.

Keywords: Children, Trauma, Tranexamic acid

* Correspondence: dnishijima@ucdavis.edu1Department of Emergency Medicine, UC Davis School of Medicine, 4150 V.Street, PSSB 2100, Sacramento, CA 95817, USAFull list of author information is available at the end of the article

© The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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BackgroundTrauma is the leading cause of morbidity and mortality inchildren in the United States [1]. Deaths from pediatrictrauma are primarily from direct injury to critical organs(brain, heart, lungs) or hemorrhage into the thoracic and/or abdominal cavities. In the initial 24 h after injury,hemorrhage is the leading cause of death [2]. The degreeof hemorrhage is influenced by both the extent of injuryto the structures and the occurrence of trauma-inducedcoagulopathy. Traumatic coagulopathy is common aftersevere injury, particularly in patients with brain injuries,acidosis, and/or shock; it independently increases the riskof morbidity and mortality [3–6]. Nearly 30% of injuredchildren admitted to the hospital have abnormalities ofroutine clotting parameters and 6% have markedly abnor-mal values [7].Hyperfibrinolysis, or the premature and excessive break-

down of blood clots, is largely driven by increased plasmingeneration after tissue injury and is a major component oftraumatic coagulopathy [8, 9]. As measured by thromboe-lastography (TEG) testing, hyperfibrinolysis occurs in 24%of severely injured children and increases the risk fordeath sixfold compared to children without hyperfibrino-lysis [10]. Hyperfibrinolysis is also associated with theneed for lifesaving interventions and the need for bloodproduct transfusions in severely injured children [11].Tranexamic acid (TXA) is an antifibrinolytic lysine

analog that inhibits plasminogen activation. Plasmin iscentral to fibrinolysis as it catalyzes the dissolution of fi-brin clots. Premature and excessive fibrinolysis is aprominent characteristic of traumatic coagulopathyand hemorrhage progression due to elevated levels oftissue plasminogen activator (tPA) commonly seenafter traumatic injuries, particularly traumatic braininjuries (TBI) [12].Recent evidence in injured adults indicates that treat-

ment with TXA decreases the risk of mortality followingtraumatic hemorrhage [13]. The Clinical Randomizationof an Antifibrinolytic in Significant Haemorrhage-2(CRASH-2) trial randomized 20,211 adult trauma pa-tients at risk for significant hemorrhage to TXA or pla-cebo. If administered within 3 h of injury, TXA reducedthe risk of death from bleeding by approximately onethird [14]. Furthermore, TXA had an excellent safetyprofile and was found to be cost-effective for use inthese injured adult patients [15]. Based on the results ofthe CRASH-2 trial, administration of TXA is consideredstandard of care for severely injured adults withhemorrhagic trauma and is included on the WorldHealth Organization’s (WHO) list of essential drugs.A similar clinical trial has not been conducted in chil-

dren with hemorrhagic injuries. We previously demon-strated that TXA is rarely given for injured children inUS children’s hospitals [16]. Data regarding TXA use in

children is mostly limited to those undergoing certainelective surgeries, specifically cardiac surgery [17–20],with some small studies in children undergoing spinaland craniofacial surgeries [17], and across a wide rangeof doses [17, 21]. These data suggest that perioperativeadministration of TXA decreases blood transfusionrequirements in children. Furthermore, these studiessuggest an excellent safety profile for TXA in children[17–20]. The type of traumatic insult and degree of in-flammation and its impact on coagulation in patientswith these elective surgeries, however, is likely differentthan that following hemorrhage from trauma.Based on the TXA studies in injured adults and the

evidence of safety and effectiveness in children undergo-ing non-traumatic surgical procedures, there is great po-tential that TXA may safely improve clinical outcomesin injured children. Not surprisingly, determining ifTXA is beneficial and safe in injured children is a toppriority for several stakeholders [6, 22–24]. To addressthis clinical question, we will conduct a pilot trial todemonstrate the ability to efficiently identify and enrollchildren with severe trauma and hemorrhagic injuriesinto a multicenter, randomized controlled trial evaluat-ing two doses of TXA and placebo.

MethodsStudy designThis pilot study is a double-blind, randomized, con-trolled trial of children younger than 18 years withhemorrhagic injuries to the torso and brain. We willenroll a maximum of 40 children during the study.Children will be randomized into one of three arms: (1)TXA dose A (15 mg/kg bolus dose over 20 min,followed by 2 mg/kg/hr infusion over 8 h), (2) TXA doseB (30 mg/kg bolus dose over 20 min, followed by 4 mg/kg/hr infusion over 8 h), and (3) normal saline placebo.This pilot study will be conducted in preparation for aconfirmatory clinical trial of TXA administration for chil-dren with hemorrhagic torso and/or brain injuries (Fig. 1).SPIRIT (Standard Protocol Items: Recommendations forInterventional Trials) guidelines were followed and achecklist completed (Additional file 1) [25].

Study settingThe pilot study will be conducted at 4 clinical sites. Allsites are American College of Surgery (ACS) verifiedLevel I pediatric trauma centers.

ParticipantsInclusion and exclusion criteriaChildren younger than 18 years with evidence ofhemorrhagic injuries to the torso and/or brain will be eli-gible. Eligible patients will be divided into three groups(head injury, torso injury, or head and torso injury) based

Fig. 1 Study objectives of the TIC-TOC pilot trial

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on the inclusion criteria listed below. Patients in the com-bined head and torso injury group must meet entry cri-teria for both head and torso trauma. See Tables 1 and 2for specific inclusion and exclusion criteria.

Participant screening and consentPrior to the onset of the study and intermittently duringits course, site clinical research coordinators and emer-gency department (ED) clinicians will be educated re-garding the trial and trained to identify potentially

Table 1 Inclusion criteria for TIC-TOC trial

Penetrating Torso Trauma:• Penetrating trauma to the chest, abdomen, neck, pelvis, or thigh withat least one of the following:◦ age-adjusted hypotension, or◦ age-adjusted tachycardia despite adequate resuscitation fluids, or◦ radiographic evidence of internal hemorrhage, or◦ clinical suspicion of ongoing internal hemorrhage

Blunt Torso Trauma:• Clinician suspicion of hemorrhagic blunt torso injury and at least oneof the following:◦ age-adjusted hypotension, or◦ persistent age-adjusted tachycardia despite adequate resuscitationfluids

• Hemothorax on chest tube placement or imaging; or• Clinical suspicion of hemorrhagic blunt torso injury and intraperitonealfluid on abdominal ultrasonography (Focused Assessment withSonography in Trauma; FAST); or

• Intra-abdominal injury on CT with either contrast extravasation or morethan trace intraperitoneal fluid; or

• Pelvic fracture with contrast extravasation or hematoma on abdominal/pelvic CT scan with at least one of the following:◦ age-adjusted tachycardia or◦ age-adjusted hypotension

Head Trauma:• GCS score 3 to 13 with associated intracranial hemorrhage on cranialCT scan

Abbreviations: CT computed tomography, GCS Glasgow Coma Scale, TOC-TOCTraumatic Injury Clinical Trial Evaluating Tranexamic Acid in Children

eligible patients. Patients will be identified and recruitedfrom the EDs of the participating centers. On arrival tothe ED, all injured children will undergo primary andsecondary surveys by the physicians providing clinicalcare in the ED. Injured children will then undergo diag-nostic testing as deemed appropriate by the treatingphysicians (i.e., standard of care). These patients will bescreened by clinical research coordinators and patientsbelieved to be eligible will be discussed with the treatingphysicians. If the patient is believed to be eligible, thecoordinator will contact the study site investigative teamto discuss eligibility. A study investigator (a clinician, de-termined by each site) will evaluate the patient and de-termine eligibility (Fig. 2). At the start of this pilot trial,we enrolled patients only if written informed consentwas obtained from parents or legal guardians. Afterstarting the trial, however, it became evident that mosteligible patients did not have a parent or legal guardian

Table 2 Exclusion criteria for TIC-TOC trial

Exclusion criteria include any of the below:1. Unable to administer study drug within 3 h of traumatic event2. Known pregnancy3. Known prisoners4. Known wards of the state5. Cardiac arrest prior to randomization6. GCS score of 3 with bilateral unresponsive pupils7. Isolated subarachnoid hemorrhage, epidural hematoma, or diffuseaxonal injury

8. Known bleeding/clotting disorders9. Known seizure disorders10. Known history of severe renal impairment11. Unknown time of injury12. Previous enrollment into the TIC-TOC trial13. Prior TXA for current injury14. Non-English and non-Spanish speaking15. Known venous or arterial thrombosis

Abbreviations: GCS Glasgow Coma Scale, TOC-TOC Traumatic Injury Clinical TrialEvaluating Tranexamic Acid in Children, TXA tranexamic acid

Fig. 2 Study enrollment procedures. Abbreviations: EFIC exception from informed consent (enrollment without in emergency scenarios whenprospective informed consent is not possible); ED emergency department; TXA tranexamic acid

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available to provide written informed consent at the timeof ED presentation and study eligibility. We therefore re-vised the protocol to include Exception from InformedConsent (EFIC) procedures if the parent or legal guard-ian was not available to provide written informed con-sent at the time of study eligibility.

InterventionsEnrolled patients will be randomized to one of threestudy arms: TXA dose A, TXA dose B, or placebo. Asystematic review demonstrated substantial variability inTXA dosing for pediatric surgical patients, ranging frominitial loading doses of 2 to 100 mg/kg intravenously(IV), and a continuous infusion ranging from 3 to10 mg/kg/h [17]. Doses selected for this study and ra-tionale are as follows:

� TXA dose A arm: Patients will receive a 15 mg/kgbolus of TXA over 20 min followed by a 2 mg/kg/hinfusion over 8 h. The maximum bolus dose is1000 mg, the maximum rate of infusion is 50 mg/min,and the maximum total maintenance dose is 1000 mg.This represents a total TXA dose of 31 mg/kg. Thisdosing is based on the CRASH-2 trial and has beenrecommended by a prior evidence statement [26].This dose is also estimated to inhibit approximately80% of fibrinolysis based on prior TXA studies [27].

� TXA dose B arm: Patients will receive a 30 mg/kg bolus of TXA over 20 min followed by a4 mg/kg/h infusion over 8 h. The maximum bolusdose is 2000 mg, the maximum rate of infusion is100 mg/min, and the maximum total maintenancedose is 2000 mg. This represents a total dose ofTXA of 62 mg/kg. This represents approximatelythe 75th percentile dosage for children receivingTXA for non-traumatic surgical procedures [16]and is estimated to inhibit 100% of fibrinolysis[27]. This dose is also within the range recommendedby theWHO [28] and has not demonstrated an increasein adverse events (compared to lower doses) [17].

� Placebo arm: Patients in the placebo group willreceive a bolus dose of normal saline over 20 minfollowed by a normal saline infusion over 8 h (in thesame weight- based volume as the other study arms).

The study drug will be discontinued if any of thefollowing occur: suspected anaphylactic reaction, se-vere renal impairment (creatinine clearance less than29 mL/min/1.73m2) is identified on subsequent la-boratory measurements, withdrawal of consent by thepatient’s legal guardian or legally authorized repre-sentative, or discovery of new information whichmakes the patient ineligible to continue participationin the study.

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Both study patients and study team members areblinded to the interventional arm. Blinding is providedby the use of identical study drugs, packaging, volume,and rates of infusion. Unblinding will not be allowed asthere is no reversal agent for TXA. Clinicians will beasked to assume the patient has received TXA and treataccordingly.

RandomizationDue to the narrow window of efficacy of TXA based onthe CRASH-2 trial, randomization must only minimallydelay treatment. To complete the randomization quickly,the study intervention will be pre-assigned using a cen-tral randomization process. Prior to enrollment at eachsite, a study drug box containing a vial of masked studydrug with a numeric identification code correspondingto the treatment assignment will be designated.Because we will be evaluating TXA for different injury

patterns (hemorrhagic torso injury, hemorrhagic braininjury, and combined hemorrhagic torso and brain injur-ies), randomization will be stratified by injury pattern.Eligible patients will be randomized into one of the threearms in a 1:1:1 ratio (TXA dose A, TXA dose B, or pla-cebo). We will perform permuted-block randomizationacross injury pattern (i.e., torso or brain or both torsoand brain). To ensure a sufficient number of injurytypes, we will limit the enrollment of patients meetingthe inclusion criteria for isolated brain injury to 20patients (as it is anticipated these will be the mostcommon eligible patients evaluated at the participat-ing sites). A patient is considered enrolled whenrandomization occurs.

OutcomesWe will collect the following outcome data: the PediatricQuality of Life Inventory (PedsQL) score, the PediatricGlasgow Outcome Scale - Extended (GOS-E Peds) score,digit span recall (a test of working memory), total bloodproducts (ml/kg) transfused over the initial 48 h of care(children with torso injuries), intracranial hemorrhageprogression in first 24 h (children with brain injuries),coagulation biomarkers, and adverse events.We will assess neurocognitive functioning and other

quality-of-life measures using the PedsQL and theGOS-E Peds 1 week, 1 month, 3 months, and 6 monthsafter ED presentation for all enrolled children (Fig. 3).We will assess working memory using the digit span re-call test 1 week, 1 month, 3 months, and 6 months afterED presentation for all enrolled children 3 years and older.Blood product transfusion will be calculated as the totalml/kg blood products received from randomization to48 h after randomization. Blood products in the calcula-tion will include red blood cell components, platelet com-ponents, plasma components, and cryoprecipitate. Prior

to study initiation, collaborating trauma surgeons, transfu-sion medicine physicians, pediatric critical care physicians,pediatric anesthesiologists, and pediatric emergencymedicine physicians will establish general guidelines forindications and thresholds for blood product transfusion.We will perform non-contrast cranial computed tomog-raphy (CT) scans 24 (± 6) hours after randomization toassess intracranial hemorrhage progression (for those whohave not received a second CT scan during the specifiedtime frame in the course of clinical care). We will excludethose who received a neurosurgical intervention from as-sessment of the 24 h CT scan. Additional brain-imagingstudies may be performed at the discretion of the treatingphysician as a part of routine care. A study neuroradiolo-gist, blinded to clinical data, will review cranial CT scansand calculate intracranial hemorrhage progressionusing the ABC/2 volume estimation [29]. Intracranialhemorrhage will be assessed relative to the total brainvolume (calculated by the XYZ/2 volume estimation)[30, 31]. We will also measure coagulation biomarkertests before and after study drug infusion. These testsinclude: kaolin activated TEG (measuring fibrinolysis asthe percentage of clot lysis at 30 min post-maximum clotstrength), d-dimer, tissue plasminogen activator (tPA),plasmin-antiplasmin (PAP) complex, and plasmin gener-ation. Parameters are performed at a central laboratory toeliminate inter-assay variability and to standardize testing.Safety outcomes will be assessed on the 7th day afterrandomization or at hospital discharge (whichevercomes first) via review of the electronic medical rec-ord and include:

� Thromboembolic disease: any venous or arterialthrombosis on diagnostic imaging post-randomization

� Seizures occurring within the initial 24 h of study drugadministration: clinical or electroencephalogram-documented

All study patients will be followed for 180 days afterrandomization or death, whichever comes first, regard-less of whether or not the patient has completed thestudy intervention.

Data management and safety monitoring planThe study Data Coordinating Center (at the Universityof Utah) will create the electronic data capture systemand worksheets. Data will be entered via the internetinto the electronic data capture system. Worksheets andstudy documents will be maintained in locked file cabi-nets in locked offices at each site.A trained site monitor will conduct site-monitoring

visits during the study period to ensure regulatorycompliance and patient safety, and to monitor the

Fig. 3 Schedule of evaluations. Abbreviations: Cr creatinine, CT computed tomography, GCS Glasgow Coma Scale, GOS-E Peds Pediatric GlasgowOutcome Scale – Extended, Hb hemoglobin, ICP intracranial pressure, INR international normalized ratio, PedsQL Pediatric Quality of Life,TBI traumatic brain injury, TXA tranexamic acid

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quality of data collected at each enrolling site. Thesite monitor will provide each site with a written re-port, and sites will be required to follow-up on anydeficiencies.The study will have a Data Safety Monitoring Board

(DSMB) approved by the funding agency to advise thesponsors and principal investigators regarding the

continuing safety of study patients and the continuing sci-entific merit of the study. The DSMB will have a charter,approve the protocol prior to implementation, and will re-view interim analyses as applicable. The DSMB is respon-sible for monitoring accrual of study patients, ensuringadherence to the study protocol, assessing data quality,reviewing the performance of individual clinical sites, and

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monitoring serious adverse events and other patient safetyissues. The DSMB will include a biostatistician, an ethicist,a pediatric trauma surgeon, a pediatric neurosurgeon, apatient advocate, and an emergency medicine physician.

Statistical considerationsAs this study is a pilot trial to assess the feasibility ofstudy procedures, the study is not powered for a particu-lar endpoint. We estimate that there will be 1.25 eligiblepatients per site per month. This eligibility rate wouldjustify the feasibility of conducting a subsequent con-firmatory clinical trial evaluating the safety and efficacyof TXA in severely injured children. We will also evalu-ate the feasibility of enrolling patients with parent orlegal guardian written informed consent only. If theseconsent procedures are not feasible (particularly giventhe 3 h from time of injury enrollment window and thefrequent absence of parents/guardians at the time of EDpresentation and study eligibility), we will apply to useEFIC procedures if parents or legal guardians are notavailable to provide written informed consent. We set apriori thresholds for recruitment futility to convert tothe use of EFIC for patient enrollment. We will collectdetailed information on missed eligible patients to evalu-ate the feasibility of consent processes to determine ifand when to initiate EFIC procedures. Ultimately our apriori thresholds to convert to EFIC procedures weremet. Our trial protocol was revised to include EFIC pro-cedures if parents or guardians are not available or ableto provide written informed consent.

DiscussionThe primary objective of this pilot trial is to assess theoverall feasibility for a subsequent, confirmatory clinicaltrial evaluating the efficacy of TXA in children with se-vere hemorrhagic injuries. We designed the pilot trial tomirror closely the subsequent confirmatory trial regard-ing study design, interventional arms, procedures, andoutcome measures. Real-world implementation of thestudy protocol will allow for assessment of various as-pects of the pilot trial. This will provide critical informa-tion on the number of eligible patients at study sites,feasibility of timely consent and enrollment procedures,and protocol adherence and variability of care. Althoughwe will not use the results of this pilot trial to estimatesample size for the subsequent confirmatory trial, wewill assess the feasibility of obtaining various outcomemeasurements to help inform the subsequent trial.Clinical trials of critically ill children are typically more

challenging compared to similar trials in adults. Pediatrictrials draw from a smaller patient pool compared toadult trials, making it more difficult to recruit adequatenumbers of subjects [32]. Issues regarding parental con-sent and child assent often lead to variability in consent

processes and local ethic committee reviews [32, 33].The many administrative tasks such as Institutional Re-view Board (IRB) approvals and consortium agreementscan delay the start of projects and increase costs[34–36]. These challenges have led to an inadequatenumber of pediatric clinical trials [19]. Specificallyfor the evaluation of TXA in trauma, there are currently10 completed or open clinical trials in adults withhemorrhagic trauma but none in children [37].Although specific strategies have been recommended

to improve the efficiency of clinical trials, it is often diffi-cult for investigators to identify all the potential obsta-cles to optimize trial efficiency before actually startingthe trial [38–40]. Premature closure of phase III clinicaltrials due to insufficient patient accrual wastes substan-tial time and resources [41, 42]. Pilot trials, designed toenroll a small number of patients with the primary goalof assessing the feasibility of a subsequent phase III trial,provide a less expensive alternative to embarking on acostly, large-scale trial [43]. Pilot studies conducted priorto definitive studies are particularly crucial in clinicaltrials of critically ill children, which by nature are atrisk for low patient accrual and complex regulatoryrequirements.Previous pediatric pilot studies have provided clear an-

swers regarding the feasibility of subsequent phase IIItrials. The Thrombolysis in Pediatric Stroke (TIPS) trialwas a phase I trial funded by the National Institute forNeurological Disorders and Stroke (NINDS) to assesstreatment with intravenous tPA in children with acuteischemic stroke [32]. Despite more than 200 meetingsand 3 years of preparation, the trial was prematurelystopped due to lack of patient accrual. Only one patientwas enrolled in the 17 active sites (median time active,9 months). Other issues identified in the trial includeddelays for human subjects approval, costs for tPA stor-age, and availability of tPA at study site pharmacies. Incontrast, the Therapeutic Hypothermia After PediatricCardiac Arrest (THAPCA) trial conducted a pilot phaseto assess the feasibility of the larger scale trial [44]. TheNational Heart, Lung, and Blood Institute (NHLBI) rec-ommended an 18-month pilot phase prior to two largertrials (one for in-hospital cardiac arrest and one forout-of-hospital cardiac arrest) due to concerns regardingthe complexities of the trials, proposed costs, the feasi-bility of the consent process, and the ability to obtainlong-term follow-up in critically ill children [44]. Ultim-ately, the pilot phase demonstrated successful recruit-ment (threshold attained 4 months ahead of schedule)and included four protocol amendments to augment en-rollment. The full-scale THAPCA trials were subse-quently approved and completed [45].We acknowledge certain limitations of our pilot trial.

We initially designed this trial using federal EFIC

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procedures; however, we were advised by the Food andDrug Administration (FDA) to initiate the pilot trial en-rolling only with written informed consent. After thepilot study started, it became evident that most eligible pa-tients did not have parents or legal guardians available toprovide written informed consent. The FDA subsequentlyallowed EFIC procedures if eligible patients did not haveparents or legal guardians available to provide written in-formed consent at the time of ED presentation and studyeligibility. The unavailability of parents or legal guardiansto provide written informed consent for injured childrenin our trial is consistent with prior literature. Approxi-mately half of children with moderate-to-severe TBI donot have their guardian present in the ED in the first 3 hafter injury [46]. Future work is planned to qualitativelyand quantitatively evaluate parent or legal guardian per-spectives regarding informed consent procedures for en-rolling severely injured children into clinical trials.Another potential limitation is that the results of the pilottrial may not be generalizable to a much larger number ofclinical sites for the subsequent confirmatory study. How-ever, because the pilot trial is being conducted at four clin-ical sites, with each site bringing its own demographic,geographic, and clinical diversity to the trial, we feel thatwe will be able to better anticipate potential barriers forthe subsequent trial. Moreover, prior to the start of thepilot trial, we will have established general guidelines forblood transfusion and neurosurgical management that willbe standardized across clinical sites.In conclusion, this pilot trial will be the first random-

ized clinical trial to evaluate TXA in children with severetrauma and hemorrhagic injuries. The results of thispilot trial will provide crucial preliminary information toconduct a confirmatory trial.

Trial statusThis manuscript is based on protocol version 2.03 (August22, 2018). The trial opened for enrollment in July 2018and we anticipate the trial will be completed by December2019.

Additional file

Additional file 1: SPIRIT 2013 Checklist: recommended items to addressin a clinical trial protocol and related documents. (DOCX 63 kb)

AbbreviationsACS: American College of Surgery; CRASH-2: Clinical Randomization of anAntifibrinolytic in Significant Haemorrhage; CT: Computed tomography;DSMB: Data Safety Monitoring Board; ED: Emergency department;EFIC: Exception from Informed Consent; EMSC: Emergency Medical Services forChildren; FDA: Food and Drug Administration; GOS-E Peds: Pediatric GlasgowOutcome Scale - Extended; HHS: Health and Human Services; HRSA: HealthResources and Services Administration; IRB: Institutional Review Board;IV: Intravenous; MCHB: Maternal and Child Health Bureau; NCATS: NationalCenter for Advancing Translational Sciences; NHLBI: National Heart, Lung, and

Blood Institute; NINDS: National Institute for Neurological Disorders and Stroke;PAP: Plasmin-antiplasmin; PedsQL: Pediatric Quality of Life; TBI: Traumatic braininjury; TEG: Thromboelastography; THAPCA: Therapeutic Hypothermia AfterPediatric Cardiac Arrest; TIC-TOC: Traumatic Injury Clinical Trial EvaluatingTranexamic Acid in Children; TIPS: Thrombolysis in Pediatric Stroke; tPA: Tissueplasminogen activator; TXA: Tranexamic acid; WHO: World Health Organization

AcknowledgementsOther authors to be included as part of the TIC-TOC Collaborators:University of California, DavisMarike ZwienenbergJoseph GalanteJoseph StephensonAlfred F. TrappeyJordan SandhuUniversity of UtahT. Charles CasperStephen FentonDoug BrockmeyerTheodore PysherChildren’s Hospital of PhiladelphiaMichael L. NanceShih-Shan Lang ChenDeborah Sesok-PizziniNationwide Children’s HospitalRaj ThakkarEric SribnikKathleen Nichol

FundingResearch reported in this publication was supported by the National Heart,Lung, and Blood Institute (NHLBI) of the National Institutes of Health underAward Number R34HL135214. Additional support has been provided by theUtah Trial Innovation Center funded by the National Center for AdvancingTranslational Sciences (NCATS) under cooperative agreement U24TR001597.The content is solely the responsibility of the authors and does not necessarilyrepresent the official views of the National Institutes of Health. This project isalso supported in part by the Health Resources and Services Administration(HRSA), Maternal and Child Health Bureau (MCHB), Emergency Medical Servicesfor Children (EMSC) Network Development Demonstration Program undercooperative agreements U03MC00008, U03MC00001, U03MC00003,U03MC00006, U03MC00007, U03MC22684, and U03MC22685. This informationor content and conclusions are those of the author and should not beconstrued as the official position or policy of, nor should any endorsements beinferred by HRSA, Health and Human Services (HHS) or the US Government.The funding organizations had no role in the design and conduct of the study;collection, management, analysis, and interpretation of the data; preparation,review, or approval of the manuscript; and decision to submit the manuscriptfor publication.

Availability of data and materialsNot applicable.

Authors’ contributionsDKN and NK conceived the study, designed the trial, and obtained researchfunding. All authors participated in protocol development and quality controlmeasures. JVB, TCC, and JMD provided statistical advice on study design. DKNdrafted the manuscript, and all authors contributed substantially to its revision.DKN and NK take responsibility for the manuscript as a whole. All authors readand approved the final manuscript.

Ethics approval and consent to participateThe study was approved by the IRBs at all study sites (central IRB number00099274 [University of Utah]).

Consent for publicationNot applicable.

Competing interestsThe authors declare that they have no competing interests at this time.

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Publisher’s NoteSpringer Nature remains neutral with regard to jurisdictional claims inpublished maps and institutional affiliations.

Author details1Department of Emergency Medicine, UC Davis School of Medicine, 4150 V.Street, PSSB 2100, Sacramento, CA 95817, USA. 2Department of Pediatrics,University of Utah School of Medicine, 295 Chipeta Way, Salt Lake City, UT84108, USA. 3Department of Pediatrics, Division of Pediatric EmergencyMedicine, University of Utah School of Medicine, Primary Children’s Hospital,100 N. Mario Capecchi Dr., Salt Lake City, UT 84113, USA. 4Department ofPediatrics, Division of Pediatric Emergency Medicine, Perelman School ofMedicine at the University of Pennsylvania, Children’s Hospital ofPhiladelphia, 3401 Civic Center Blvd., Philadelphia, PA 19104, USA.5Department of Pediatrics, Division of Pediatric Emergency Medicine, OhioState University School of Medicine, Nationwide Children’s Hospital, 700Children’s Dr., Columbus, OH 43205, USA. 6Department of PediatricNeurosciences, Barrow Neurological Institute at Phoenix Children’s Hospital,1919 E. Thomas Rd, Phoenix, AZ 85016, USA. 7Department of Pathology andLaboratory Medicine, UC Davis School of Medicine, 2315 Stockton Blvd.,Sacramento, CA 95817, USA. 8Department of Radiology, UC Davis School ofMedicine, 2315 Stockton Blvd., Sacramento, CA 95817, USA. 9Department ofPsychology, University of California, Davis, 102K Young Hall, 1 Shields Ave.,Davis, CA 95616, USA. 10Department of Population Health, London School ofHygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK.11Department of Orthopedics and Rehabilitation, University of Wisconsin, 317Knutson Drive, Madison, WI 53704, USA. 12Department of Pathology andLaboratory Medicine, University of California, Davis, 3422 Tupper Hall, Davis,CA 95616, USA. 13Departments of Emergency Medicine and Pediatrics, UCDavis School of Medicine, 4150 V. Street, PSSB 2100, Sacramento, CA 95817,USA.

Received: 12 April 2018 Accepted: 10 October 2018

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